Articular chondrocytes from aging rats respond poorly to insulin-like growth factor-1: an altered signaling pathway

• Published in: Mechanisms of ageing and development 2000-05, Vol.115 (1), p.21-37
• Main Authors: Messai, Habib, Duchossoy, Yann, Khatib, Abdel-Majid, Panasyuk, Andrei, Mitrovic, Dragoslav R.
• Format: Article
• Language: English
• Subjects: Aggrecans; Aging - physiology; Animals; Animals, Newborn - growth & development; Animals, Newborn - physiology; cAMP; Cartilage, Articular - cytology; Cartilage, Articular - drug effects; Cartilage, Articular - metabolism; Cells, Cultured; Collagen - biosynthesis; Collagen - genetics; Collagen synthesis; Cyclic AMP - biosynthesis; Cyclic AMP - genetics; DNA - biosynthesis; DNA synthesis; Extracellular Matrix Proteins; Gene Expression - physiology; Insulin-Like Growth Factor I - pharmacology; Lectins, C-Type; Male; Phorbol ester-PMA; PKC; Proteoglycan synthesis; Proteoglycans - biosynthesis; Proteoglycans - genetics; Rats; Rats, Wistar; Signal Transduction - physiology; Tetradecanoylphorbol Acetate - pharmacology; Thymidine - metabolism
• ISSN: 0047-6374; 1872-6216
• DOI: 10.1016/S0047-6374(00)00107-X

This study investigates the effect of insulin-like growth factor-1 (IGF-1) and phorbol 12-myrystate 13-acetate (PMA) on 3H-thymidine, 35SO 4 and 3H -glycine incorporations, adenosine 3′:5′-cyclic monophosphate (cAMP) production and protein kinase C (PKC) activation in cultured rat articular chondrocyte monolayers (RACM) derived from animals of different ages. It was found that IGF-1 stimulates all these cellular functions in cultures derived from all age groups in a concentration dependent manner, although the cells from 14-month old animals responded poorly. IGF-1 also induces in cells from 1-month old rats an increase in the expression of mRNAs specific for aggrecan and type II collagen molecules as shown with RT-PCR. These effects are mediated via IGF-1 interaction with specific receptors because the monoclonal antibody against the receptor protein suppresses more than 60% of the ligand-induced DNA synthesis. PMA, a direct PKC activator, potentiated IGF-1-induced effects in all cells but much more strongly in cells from young than in cells from 14-month old animals. The age-related failure of RACM to respond adequately to IGF-1 was correlated with a decrease in IGF-1-induced cAMP production, and IGF-1-induced and PMA-induced PKC activations. These results show that IGF-1 regulates the synthesis of DNA, proteoglycans (PG) and collagen II at the level of transcription and suggest that the reduced response of cell monolayers derived from 14-month old rats to IGF-1 is probably due to a failure of old cells to adequately transduce IGF-1 receptor-generated downstream signaling.